Empagliflozin 通过增强心肌能量学改善非糖尿病性心力衰竭的不良左心室重构,Journal of the American College of Cardiology

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Empagliflozin 通过增强心肌能量学改善非糖尿病性心力衰竭的不良左心室重构
Journal of the American College of Cardiology ( IF 21.7 ) Pub Date : 2019-04-01 , DOI: 10.1016/j.jacc.2019.01.056
Carlos G Santos-Gallego ₁ , Juan Antonio Requena-Ibanez ₂ , Rodolfo San Antonio ₃ , Kiyotake Ishikawa ₄ , Shin Watanabe ₄ , Belen Picatoste ₅ , Eduardo Flores ₃ , Alvaro Garcia-Ropero ₁ , Javier Sanz ₄ , Roger J Hajjar ₄ , Valentin Fuster ₄ , Juan J Badimon ₁

Affiliation

背景 EMPA-REG OUTCOME（2 型糖尿病患者的 Empagliflozin 心血管结局事件试验）试验中的 Empagliflozin 心脏益处不能完全用其抗高血糖活性来解释。目标假设是，empagliflozin 的心脏益处是通过将心肌燃料代谢从葡萄糖转向酮体 (KB) 来介导的，这可改善心肌能量产生。方法在非糖尿病猪 (n = 14) 中通过近端左前降支动脉球囊闭塞 2 小时诱发心力衰竭。动物随机接受恩格列净或安慰剂治疗 2 个月。用心脏磁共振成像和 3 维超声心动图对动物进行评估。通过同时从冠状动脉和冠状窦取样分析心肌代谢物消耗。获得心肌样品用于分子评估。非心肌梗塞动物用作比较。结果尽管两组的初始缺血性心肌损伤相似，但与对照组相比，恩格列净组在 2 个月时显示出不良重构的改善（左心室 [LV] 质量降低、LV 扩张减少、LV 球形度降低）。LV 收缩功能（LV 射血分数和超声心动图衍生的应变）得到改善，神经激素激活也得到改善。与非心肌梗死相比，对照动物主要通过无氧糖酵解增加心肌葡萄糖消耗，同时减少游离脂肪酸 (FFA) 和支链氨基酸 (BCAA) 的利用。Empagliflozin 治疗的猪不消耗葡萄糖（减少心肌葡萄糖摄取和葡萄糖相关酶），而是转向利用 KB、FFA 和 BCAA（增加这 3 种代谢物的心肌摄取，并增强酶的表达/活性与 KB/FFA/BCAA 的代谢有关）。Empagliflozin增加心肌ATP含量，增强心肌工作效率。结论 Empagliflozin 可改善非糖尿病猪模型中的不良心脏重构和心力衰竭。Empagliflozin 将心肌燃料利用从葡萄糖转向 KB、FFA 和 BCAA，从而改善心肌能量，增强 LV 收缩功能，并改善不良的 LV 重构。和葡萄糖相关酶），而是转向利用 KB、FFA 和 BCAA（增加这 3 种代谢物的心肌摄取，并增强与 KB/FFA/BCAA 代谢有关的酶的表达/活性）。Empagliflozin增加心肌ATP含量，增强心肌工作效率。结论 Empagliflozin 可改善非糖尿病猪模型中的不良心脏重构和心力衰竭。Empagliflozin 将心肌燃料利用从葡萄糖转向 KB、FFA 和 BCAA，从而改善心肌能量，增强 LV 收缩功能，并改善不良的 LV 重构。和葡萄糖相关酶），而是转向利用 KB、FFA 和 BCAA（增加这 3 种代谢物的心肌摄取，并增强与 KB/FFA/BCAA 代谢有关的酶的表达/活性）。Empagliflozin增加心肌ATP含量，增强心肌工作效率。结论 Empagliflozin 可改善非糖尿病猪模型中的不良心脏重构和心力衰竭。Empagliflozin 将心肌燃料利用从葡萄糖转向 KB、FFA 和 BCAA，从而改善心肌能量，增强 LV 收缩功能，并改善不良的 LV 重构。Empagliflozin增加心肌ATP含量，增强心肌工作效率。结论 Empagliflozin 可改善非糖尿病猪模型中的不良心脏重构和心力衰竭。Empagliflozin 将心肌燃料利用从葡萄糖转向 KB、FFA 和 BCAA，从而改善心肌能量，增强 LV 收缩功能，并改善不良的 LV 重构。Empagliflozin增加心肌ATP含量，增强心肌工作效率。结论 Empagliflozin 可改善非糖尿病猪模型中的不良心脏重构和心力衰竭。Empagliflozin 将心肌燃料利用从葡萄糖转向 KB、FFA 和 BCAA，从而改善心肌能量，增强 LV 收缩功能，并改善不良的 LV 重构。

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Empagliflozin Ameliorates Adverse Left Ventricular Remodeling in Nondiabetic Heart Failure by Enhancing Myocardial Energetics

BACKGROUND Empagliflozin cardiac benefits in the EMPA-REG OUTCOME (Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients) trial cannot be explained exclusively by its antihyperglycemic activity. OBJECTIVES The hypothesis was that empagliflozin's cardiac benefits are mediated by switching myocardial fuel metabolism away from glucose toward ketone bodies (KB), which improves myocardial energy production. METHODS Heart failure was induced in nondiabetic pigs (n = 14) by 2-h balloon occlusion of the proximal left anterior descending artery. Animals were randomized to empagliflozin or placebo for 2 months. Animals were evaluated with cardiac magnetic resonance imaging and 3-dimensional echocardiography. Myocardial metabolite consumption was analyzed by simultaneous blood sampling from coronary artery and coronary sinus. Myocardial samples were obtained for molecular evaluation. Nonmyocardial infarction animals served as comparison. RESULTS Despite similar initial ischemic myocardial injury in both groups, the empagliflozin group showed amelioration of adverse remodeling at 2 months (lower left ventricular [LV] mass, reduced LV dilatation, less LV sphericity) versus the control group. LV systolic function (LV ejection fraction and echocardiography-derived strains) was improved, as was neurohormonal activation. Compared with nonmyocardial infarction, control animals increased myocardial glucose consumption mainly through anaerobic glycolysis while reducing utilization of free fatty acid (FFA) and branched-chain amino acid (BCAA). Empagliflozin-treated pigs did not consume glucose (reduction in myocardial glucose uptake, and glucose-related enzymes) but instead switched toward utilization of KB, FFA, and BCAA (increased myocardial uptake of these 3 metabolites, and enhanced expression/activity of the enzymes implicated in the metabolism of KB/FFA/BCAA). Empagliflozin increased myocardial ATP content and enhanced myocardial work efficiency. CONCLUSIONS Empagliflozin ameliorates adverse cardiac remodeling and heart failure in a nondiabetic porcine model. Empagliflozin switches myocardial fuel utilization away from glucose toward KB, FFA, and BCAA, thereby improving myocardial energetics, enhancing LV systolic function, and ameliorating adverse LV remodeling.

更新日期：2019-04-01

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